7-Methoxy cyclonexadienylureidocephalosporins

ABSTRACT

Compounds of the formula ##SPC1## 
     Wherein Y is H, lower alkyl or lower alkoxy, R 2  and R 3  each are H or lower alkyl, n is 0-3 and R is H or ##EQU1## or S-heterocyclic, and pharmaceutically acceptable salts and esters thereof are effective antibacterial agents. In general the preferred products are those wherein the methoxy group is designated the α configuration.

BACKGROUND OF THE INVENTION

Derivatives of 6-aminopenicillanic acid and of 7-aminocephalosporanicacid are known and have been described as antibacterial agents. Thereis, however, a continuing need for new antibacterial agents which areeffective against additional gram-positive and gram-negative organisms,are effective against resistant organisms or which may be utilized whenbacteria develop resistance to known antibacterial agents, or which areparticularly effective against certain hard to control organisms.

SUMMARY OF THE INVENTION

This invention relates to new 7-methoxycyclohexadienylureidocephalosporins of the general formula ##SPC2##

Wherein Y is hydrogen or alkyl or alkoxy each of 1 to 4 carbons, R² andR³ each are H or alkyl of 1 to 4 carbons, n is 0, 1, 2 or 3, and R is H,##STR1## pyridinyl-1-oxo-2-thio; 3-methyl-1,2,4-thiadiazolylthio;1-methyltetrazolyl-5-thio; 2-methyl-1,3,4-thiadiazolyl-5-thio, ##STR2##or pyridinium and to pharmaceutically acceptable carboxylate salts,lower alkyl esters, or acyloxymethyl esters thereof. The compounds ofthe present invention are effective antibacterial agents and are usefulin the treatment of many gram negative and gram positive infections.These compounds are useful as disinfectants and also as nutritionalsupplements in animal feeds. The 7-methoxy group occupies theα-configuration.

DETAILED DESCRIPTION

The compounds of the present invention may be prepared by coupling anactivated form of a cyclohexadienyl-α-aminoalkanoic acid of the formula##SPC3##

Wherein Y, n, R², R³ and R⁴ are as defined above with a protected esterof 7-amino-7-methoxycephalosporanic acid (7-AMCA) or of7-amino-7-methoxy-3-desacetoxycephalosporanic acid (7-AMDCA) and thenreacting the product with an alkali metal cyanate or an alkaline earthmetal cyanate. For the purpose of this invention, the 7-AMCA or 7-AMDCAcompound chosen is that with the α-configuration of the 7-methoxy group.The starting materials of formula II may be prepared by reducing acompound of the formula ##SPC4##

Or a metal salt thereof, e.g., alkali metal salt, alkaline earth metalsalt or the like, with sodium or lithium in liquid ammonia followed bytreatment with an alcohol such as ethanol, t-butanol, followed bytreatment with ammonium chloride, or other amine hydrochloride.

A compound of formula II, produced by any suitable method, for example,that described above, is then reacted with an alkali metal cyanate or analkaline earth metal cyanate to form an α-ureido compound of the formula##SPC5##

This reaction takes place by treating an aqueous suspension of theα-amino acid with the alkali or alkaline earth metal cyanate.Acidification with hydrochloric acid precipitates the α-ureido acid ingood yield. A solution of the α-ureido acid in an organic solventcontaining a tri-(lower)alkyl amine is converted to a mixed carbonic orother anhydride by treating with an anhydride forming reagent, e.g., alower alkyl chloroformate, an aryl chloroformate, or an acyl halide, atreduced temperatures of from about 0° C to about -20° C.

Reaction at reduced temperatures of the mixed anhydride with a protectedester of 7-amino-7-methoxycephalosporanic acid (7-AMCA) or a protectedester of 7-amino-7-methoxy-3-desacetoxy-cephalosporanic acid (7-AMDCA)or a protected ester of a compound of formula V ##SPC6##

yields the compounds I of the present invention wherein R is acetoxy, H,or carbamoyloxy respectively, after removal of the ester protectinggroup.

Alternatively, a compound of formula I may be obtained by converting acompound of formula IV to an activated ester or by reacting a compoundof formula IV with a carboxyl group activating agent, such as, forexample, dicyclohexylcarbodiimide or bisimidazole carbonyl, and thencoupling the activated form of the compound of formula IV with aprotected ester of 7-AMCA or a protected ester of 7-AMDCA. In somecases, as will be obvious to those skilled in the art, the carboxylgroup may be activated by conversion to an acid halide, e.g., thechloride, or to an azide prior to coupling with a protected ester of7-AMCA or a protected ester of 7-AMDCA. A more detailed discussion ofcarboxyl activating groups may be obtained by reference to standardworks on peptide synthesis, for example, Bodanszky et al., "PeptideSynthesis", Interscience, 1966.

Alternatively, the α-amino acid of formula II may be used to acylate aprotected ester of 7-AMCA or a protected ester of 7-AMDCA. The resultingα-amino acid derivative of a protected ester of 7-AMCA or a protectedester of 7-AMDCA is then reacted with an alkali metal cyanate or analkaline earth metal cyanate in the presence of water and the estergroup removed to form the compounds I of the present invention.

The α-amino acid (II) or the α-ureido acid IV obtained occurs as aracemate of d and l optical isomers. It is generally possible to resolvethese compounds by using optically pure bases (or acids) using methodsknown to the art, for example, as described by L. Velluz, "SubstancesNaturelle de Synthesese," 9, pp. 119-174 (1954), or E. L. Eliel,"Stereochemistry of Carbon Compounds," Chapter 4, McGraw-Hill Book Co.,N.Y. (1962). The resulting pure d or l acid may then be coupled to the7-AMCA or 7-AMDCA moiety. Generally the coupling of the d form leads tothe more active product.

When preparing compounds of the present invention according to thereaction sequence wherein an α-amino acid is acylated with a protectedester of 7-AMCA or a protected ester of 7-AMDCA, it may be desirable toprotect the α-amino group during the acylation reaction by means of anamino protecting group. Such amino protecting groups are well known inthe art and are described, for example, by Bodanszky et al., "PeptideSynthesis," supra.

Specific examples of methods for acylating the protected ester of 7-AMCAor a protected ester of 7-AMDCA are similar to those described for theacylation of 7-ACA or 7-ADCA, for example, in Netherlands Pat. No.6,812,382, Belgian Pat. No. 675,298, as well as in the followingarticles:

Spencer et al., J. Med. Chem., 9, 746 (1966);

Ryan et al., ibid. 12, 310 (1969).

Compounds of formula V wherein R is heterocyclylthio or pyridinium maybe obtained from an acylated 7-AMCA by methods known in the art for theformation of 7-aminocephalosporanic acid analogs, e.g., Abraham andNewton (1950) Ciba Foundation Symposium, Amino Acids, Peptides,Antimetabolic Acitivity, p. 205; U.S. Pat. No. 3,225,038; and BelgianPat. Nos. 641,338 and 652,148.

The carboxylate salts of the compounds (I) of the present invention areformed by reacting the carboxyl group of the 7-AMCA or 7-AMDCA moietywith a salt-forming ion, e.g., an alkali metal such as sodium orpotassium, or an alkaline earth metal such as magnesium or calcium or ametal of group IIIA such as aluminum, or the radical of an organic basesuch as dibenzylamine, N,N'-dibenzylethylenediamine or other organicbases known to form salts with cephalosporanic acids.

The lower alkyl esters may be obtained by esterifying the carboxyl groupof the 7-AMCA or 7-AMDCA moiety with a straight or branched chain loweralkyl halide of from 1 to 3 carbon atoms, e.g., methyl chloride, ethylbromide and the like, or with a diazoalkane of from 1 to 3 carbon atoms,e.g., diazomethane, diazoethane, and the like. The resulting ester groupis then formed by a radical such as methyl, ethyl, propyl or isopropyl.

The acyloxymethyl esters may be obtained according to known methods, forexample a method adapted from that of Daehne et al., J. Med. Chem. 13,607 (1970), by reacting the carboxyl group or a metal salt thereof of acompound of formula I with a halide of the formula ##STR3## wherein R'may be lower alkyl of up to 5 carbon atoms, phenyl, benzyl or phenethyl,and X is chlorine or bromine. Thus, suitable compounds includeacetoxymethyl chloride, propionyloxymethyl chloride, butyryloxymethylchloride, pivaloyloxymethyl chloride, valeryloxymethyl chloride,benzoyloxymethyl chloride, or phenacetoxymethyl chloride, and the like.

It will be appreciated that certain of the compounds of this inventionexist in various states of solvation as well as in different opticallyactive forms. The various forms as well as their mixtures are within thescope of this invention.

The compounds of this invention have a broad spectrum of antibacterialactivity against both gram positive and gram negative organisms such asStaphylococcus aureus, Salmonella schottmuelleri, Proteus vulgaris,Escherichia coli and Streptococcus pyogenes. They may be used asantibacterial agents in a prophylactic manner, e.g., in cleaning ordisinfecting compositions, or otherwise to combat infections due toorganisms such as those named above, and in general may be utilized in amanner similar to cephalosporin C, cephalothin and other cephalosporins.For example, a compound of formula I or a physiologically acceptablesalt or ester thereof may be used in various animal species in an amountof about 1 to 200 mg./kg. daily, orally or parenterally, in single ortwo to four divided doses to treat infections of bacterial origin.

Up to about 600 mg. of a compound of formula I or a pharmaceuticallyacceptable salt or ester thereof may be incorporated in an oral dosageform such as tablets, capsules or elixirs or in an injectable form in asterile aqueous vehicle prepared according to conventionalpharmaceutical practice.

In cleaning or disinfecting compositions, e.g., in barns or dairyequipment, a concentration of about 0.01 to 1% by weight of suchcompounds admixed with, suspended or dissolved in conventional inert dryor aqueous carriers for application by washing or spraying may be used.

They are also useful as nutritional supplements in animal feeds.

The compounds of the present invention in the described dosages may beadministered orally; however, other routes such as intraperitoneally,subcutaneously, intramuscularly or intravenously may be employed.

The active compounds of the present invention are orally administered,for example, with an inert diluent or with an assimilable ediblecarrier, or they may be enclosed in hard or soft gelatin capsules, orthey may be compressed into tablets, or they may be incorporateddirectly with the food of the diet. For oral therapeutic administration,the active compounds of this invention may be incorporated withexcipients and used in the form of tablets, troches, capsules, elixirs,suspensions, syrups, wafers, chewing gum, and the like. The amount ofactive compound in such therapeutically useful compositions orpreparations is such that a suitable dosage will be obtained.

The tablets, troches, pills, capsules and the like may also contain thefollowing: a binder such as gum tragacanth, acacia, corn starch orgelatin; an excipient such as dicalcium phosphate; a disintegratingagent such as corn starch, potato starch, alginic acid and the like; alubricant such as magnesium stearate; and a sweetening agent such assucrose, lactose or saccharin may be added or a flavoring agent such aspeppermint, oil of wintergreen, or cherry flavoring. When the dosageunit form is a capsule, it may contain in addition to materials of theabove type a liquid carrier such as a fatty oil. Various other materialsmay be present as coatings or to otherwise modify the physical form ofthe dosage unit, for instance, tablets, pills or capsules may be coatedwith shellac, sugar, or both. A syrup or elixir may contain the activecompounds, sucrose as a sweetening agent, methyl and propyl parabens aspreservatives, a dye and a flavoring such as cherry or orange flavor. Ofcourse, any material used in preparing any dosage unit form should bepharmaceutically pure and substantially non-toxic in the amountsemployed.

The 7-AMCA or 7-AMDCA compound or the compound of formula V selected forthe coupling reactions in the following examples are chosen with the7-α-methoxy configuration.

The following examples illustrate the present invention without,however, limiting the same thereto. All temperatures are on thecentigrade scale.

EXAMPLE 17-[2-Ureido-2-(1,4-cyclohexadienyl)acetamido]-7-methoxycephalosporanicacid

A suspension of D-2-amino-2-(1,4-cyclohexadienyl) acetic acid (0.10moles) in 150 ml. of water is treated with 8.1 g. of potassium cyanate.The resulting mixture is heated to about 80° C to give a clear solutionwhich is then allowed to stand at room temperature for about 24 hours.Acidification to pH 3.5-5 with hydrochloric acid precipitates theα-ureido compound. A solution containing 0.10 moles of the α-ureido acidin 100 ml. of acetone containing 10.1 g of triethylamine at atemperature of from about 0° C to about -20° C is converted to a mixedcarbonic anhydride by treating with 10.8 g of ethyl chloroformate forabout 30 minutes. A cold (about -10° C) solution of 0.1 Mol of7-amino-7-methoxycephalosporanic acid benzhydryl ester in 400 ml ofacetone containing 10.1 g of triethylamine is added to the solution ofmixed anhydride and the reaction mixture stirred vigorously at about 0°C for approximately 30-45 minutes. The volume of the solution is reducedby evaporating the bulk of the acetone at reduced pressure at roomtemperature or below. One liter of ethyl acetate is added and thesolution washed with 2 × 200 ml of ice cold 5% aqueous sodiumbicarbonate, 100 ml of water, 2 × 200 ml of 0.5 molar hydrochloric acid,and 100 ml again of water. The ethyl acetate solution is dried (Na₂ SO₄)and evaporated to deposit the benzhydryl ester of the title compound.

The free acid is obtained by dissolving the ester (1 g) and anisole (500mg) in 20 ml of ice cold trifluoroacetic acid and keeping it at 0°-5° Cfor 30 minutes. The acid solvent is evaporated at reduced pressure. Theresidue is treated with 50 ml of water and the pH adjusted to 7.5 withsodium hydroxide to dissolve the product. The solution is washed withethyl acetate. (Lyophilization of the aqueous solution deposits thesodium salt of the title compound). The aqueous layer is acidified toprecipitate the title compound.

EXAMPLE 27-[2-Ureido-2-(1,4-cyclohexadienyl)acetamido]-7-methoxy-3-desacetoxycephalosporanicacid

Following the procedure of example 1 but substituting 0.1 mol of7-amino-7-methoxy-3-desacetoxycephalosporanic acid benzhydryl ester for7-amino-7-methoxycephalosporanic acid ester, the title compound isobtained.

EXAMPLE 3 Pivaloyloxymethyl ester of7-[2-ureido-(1,4-cyclohexadienyl)acetamido]-7-methoxy-cephalosporanicacid

Chloromethylpivalate (20 mmole) is combined with 10 mmole of the productof example 1, 0.4 ml. of a 5% aqueous sodium iodide solution, and 170ml. of acetone. Triethylamine, 2.0 gm. (20 mmole), is added and themixture stirred for 10 hours, then refluxed for 1 hour. The reactionmixture is cooled and concentrated in vacuo. The residue is partitionedbetween ethyl acetate, and 5% aqueous sodium bicarbonate. The organiclayer is dried over sodium sulfate and evaporated to give the crudeproduct which is obtained as a powder upon trituration with ether.

EXAMPLE 4 Acetoxymethyl ester of7-[2-ureido-2-(1,4-cyclohexadienyl)acetamido]-7-methoxycephalosporanicacid

Following the procedure of example 3 but substituting 20 mmole of thechloromethylacetate for the chloromethylpivalate, the title compound isobtained.

EXAMPLE 57-[2-Ureido-2-(1,4-cyclohexadienyl)acetamido]-7-methoxy-3-desacetoxycephalosporanicacid, methyl ester

A 0.1 molar solution of the product of example 2 in dimethoxyethane istreated with an excess of ethereal diazomethane. Evaporation of thesolvent at reduced pressure deposits the title compound.

EXAMPLE 67-[2-Ureido-2-(1,4-cyclohexadienyl)acetamido]-7-methoxycephalosporanicacid, ethyl ester

Following the procedure of example 5 but substituting the product ofexample 1 for the product of example 2, and substituting diazoethane fordiazomethane, the title compound is obtained.

EXAMPLE 77-[2-Ureido-2-(1,4-cyclohexadienyl)acetamido]-7-methoxycephalosporanicacid, potassium salt

One millimole of the product of example 1 is dissolved in 10 ml. of a0.1 N aqueous KOH solution. Lyophilization of the solution yields thetitle compound.

EXAMPLE 87-[2-Ureido-2-(1,4-cyclohexadienyl)acetamido]-7-methoxy-3-desacetoxy-cephalosporanicacid, calcium salt

One millimole of the product of example 2 is dissolved in 10 ml. of a0.05 N aqueous Ca(OH)₂ solution. Lyophilization of the solution yieldsthe title compound.

EXAMPLE 97-[2-Ureido-2-(1,4-cyclohexadienyl)acetamido]-7-methoxycephalosporanicacid, N,N'-dibenzylethylenediamine salt

A solution of 0.010 mol of the product of example 1 in 25 ml of ethanolis added to a solution of 1.20 g of N,N'-dibenzylethylenediamine in 25ml of ethanol at room temperature. After 15 minutes stirring the solventis evaporated to deposit the title compound.

EXAMPLE 107-[2-Ureido-2-(1,4-cyclohexadienyl)acetamido]-7-methoxy-3-[2-(5-methyl-1,3,4-thiadiazolyl)-thiomethyl]-Δ³-cephem-4-carboxylic acid

A solution of (0.026 mole) of the product of example 1, NaHCO₃ (2.1 g)and 3.8 g 2-mercapto-5-methyl-1,3,4-thiadiazole in 200 ml of pH 6.4phosphate buffer is stirred for 5.5 hours at 60° C. The reaction iscooled to room temperature, acidified to pH 3 and extracted with ethylacetate. The ethyl acetate layer is worked with saturated NaCl solution,dried (Na₂ SO₄) and evaporated at reduced pressure to deposit theproduct.

EXAMPLES 11 - 13

Following the procedure of example 10 but substituting for2-mercapto-5-methyl-1,3,4-thiadiazole, the heterocyclylthio compoundlisted below in column I, there is obtained respectively the finalcompound of column II

    ______________________________________                                               I               II                                                     ______________________________________                                        11. Pyridinyl-1-oxo-2-thiol                                                                       7-[2-Ureido-2-(1,4-cyclo-                                                     hexadienyl)acetamido]-7-methoxy-                          3-[2-(1-oxopyridinyl)thiomethyl]-                                                                 Δ.sup.3 -cephem-4-carboxylic acid                   12. 3-methyl-1,2,4-thia-                                                                          7-[2-Ureido-2-(1,4-cyclo-                                     diazolyl-5-thiol                                                                              hexadienyl)acetamido]-7-methoxy-                          3-[5-(3-methyl-1,2,4-thia-                                                                        diazolyl)thiomethyl]-Δ.sup.3 -                                          cephem-4-carboxylic acid                                  13. 1-methyltetrazolyl-5-                                                                         7-[2-Ureido-2-(1,4-cyclo-                                     thiol           hexadienyl)acetamido]-7-                                                      methoxy-3-[5-(1-methyltetra-                                                  zolyl)thiomethyl]-Δ.sup.3 -cephem-                                      4-carboxylic acid                                         ______________________________________                                    

EXAMPLE 147-[2-Ureido-2-(1,4-cyclohexadienyl)acetamido]-7-methoxy-3-carbamoyloxymethyl-Δ³-cephem-4-carboxylic acid

A solution containing 0.10 moles ofD-2-ureido-2-(1,4-cyclohexadienyl)acetic acid in 100 ml of acetonecontaining 10.1 g of triethylamine at a temperature of from about 0° Cto about -20° C is converted to a mixed carbonic anhydride by treatingwith 10.8 g of ethyl chloroformate for about 30 minutes. A cold (about-10° C) solution of 0.10 mol of7-amino-7-methoxy-3-carbamoyloxy-methyl-Δ³ -cephem carboxylic acid,(prepared by the method indicated in Netherlands Pat. No. 7,204,982) in400 ml of 1:1 acetone containing 10.1 g of triethylamine is added to thesolution of mixed anhydride and the reaction mixture stirred vigorouslyat about 0° C for approximately 30-45 minutes. The volume of thesolution is reduced by evaporating the bulk of the acetone at reducedpressure at room temperature or below.

One liter of ethyl acetate is added and the solution washed with 2 × 200ml of ice cold 5% aqueous sodium bicarbonate, 100 ml of water, 2 × 200ml of 0.5 molar hydrochloric acid, and 100 ml again of water. The ethylacetate solution is dried (Na₂ SO₄) and evaporated to deposit thebenzhydryl ester of the title compound.

The free acid is obtained by dissolving the ester (1 g) and anisole (500mg) in 20 ml of ice cold trifluoroacetic acid and keeping it at 0°-5° Cfor 30 minutes. The acid solvent is evaporated at reduced pressure. Theresidue is treated with 50 ml of water and the pH adjusted to 7.5 withNaOH to dissolve the product. The solution is washed with ethyl acetate.(Lyophilization of the aqueous solution deposits the sodium salt of thetitle compound). The aqueous layer is acidified to precipitate the titlecompound.

EXAMPLE 157-[2-Ureido-3-(1,4-cyclohexadienyl)propionamido]-7-methoxycephalosporanicacid

Following the procedure of example 1 but substituting an equivalentamount of 3-(1,4-cyclohexadienyl)propionic acid, the title compound isobtained.

EXAMPLE 167-[2-Ureido-3-(4-methoxy-1,4-cyclohexadienyl)propionamido]-7-methoxy-3-desacetoxycephalosporanicacid

Following the procedure of example 2 but substituting3-(4-methoxy-1,4-cyclohexadienyl)propionic acid for3-(1,4-cyclohexadienyl)propionic acid, the title compound is obtained.

EXAMPLE 177-[2-Ureido-2-(1,4-cyclohexadienyl)acetamido]-7-methoxycephalosporanicacid

A solution containing 0.10 moles of the α-ureido2-(1,4-cyclohexadienyl)acetic acid in 100 ml of acetone containing 10.1g of triethylamine at a temperature of from about 0° C to about -20° Cis converted to a mixed carbonic anhydride by treating with 10.8 g ofethyl chloroformate for about 30 minutes. A cold (about -10° C) solutionof 0.10 mol of 7-amino-7-methoxy-3-cephalosporanic acid, trichloroethylester in 400 ml of 1:1 acetone containing 10.1 g of triethylamine isadded to the solution of mixed anhydride and the reaction mixturestirred vigorously at about 0° C for approximately 30-45 minutes. Thevolume of the solution is reduced by evaporating the bulk of the acetoneat reduced pressure at room temperature or below.

One liter of ethyl acetate is added and the solution washed with 2 × 200ml of ice cold 5% aqueous sodium bicarbonate, 100 ml of water, 2 × 200ml of 0.5 molar hydrochloric acid, and 100 ml again of water. The ethylacetate solution is dried (Na₂ SO₄) and evaporated to deposit thetrichloroethyl ester of the title compound.

The free acid is obtained by dissolving the ester (1 g) in 30 ml of cold90% acetic acid at 0°-5° C for 1 hour. The acid solvent is evaporated atreduced pressure. The residue is treated with 50 ml of water and the pHadjusted to 7.5 with NaOH to dissolve the product. The solution iswashed with ethyl acetate. (Lyophilization of the aqueous solutiondeposits the sodium salt of the title compound). The aqueous layer isacidified to precipitate the title compound.

EXAMPLE 187-[2-Ureido-2-(4-methyl-1,4-cyclohexadienyl)acetamido]-7-methoxycephalosporanicacid

p-Tolualdehyde is converted to the corresponding α-amino acid by theStrecker amino acid synthesis, Ann., 75, 27 (1850); 91, 349 (1854)wherein p-tolualdehyde is reacted simultaneously with ammonia and HCNfollowed by hydrolysis of the resulting amino nitrile. A solution of the2-amino-2-(p-tolyl)acetic acid (0.07 mmole) in 900 ml distilled ammonia(which has been treated with 45 mg lithium after distillation to destroytraces of moisture) is slowly diluted with 370 ml dry t-butanol. Over aperiod of hours, 1.65 g lithium (3.27 eq.) is added in small portionsuntil a permanent blue color is obtained. The blue reaction mixture isthen treated with 38 g of triethylamine hydrochloride. The ammonia isallowed to evaporate at room temperature overnight and the residualsolvent is evaporated at reduced pressure. The white residue is taken upin a small amount of methanol-water and added to 4 l. of cold 1:1chloroform acetone to precipitate the crude product. After 20 minutesstirring the suspension is filtered and the white filter cake dried invacuo; the filter cake is then pulverized and submitted once more to theprecipitation process from 1:1 chloroform-acetone. 0.1 moles of theproduct, 2-amino-2-(4-methyl-1,4-cyclohexadienyl)acetic acid is thensubstituted for the D-2-amino-2-(1,4-cyclohexadienyl)acetic acid ofexample 1 and the procedure of that example is followed to yield thetitle compound.

EXAMPLE 19

A sterile powder for reconstitution for use intramuscularly is preparedfrom the following ingredients which supply 1000 vials each containing250 mg. of active ingredient:

    ______________________________________                                        7-[2-Ureido-2-(1,4-cyclohexadienyl)acetamido]-                                7-methoxycephalosporanic acid, Na salt,                                       sterile                     250 mg.                                           Lecithin powder, sterile    50 gm.                                            Sodium carboxymethylcellulose, sterile                                                                    20 gm.                                            ______________________________________                                    

The sterile powders are aseptically blended, subdivided, filled intosterile vials and sealed. The addition of 1 ml. of water for injectionto the vial provides a suspension for intramuscular injection.

EXAMPLE 20

Tablets are prepared from the following ingredients:

    ______________________________________                                        7-[2-Ureido-2-(1,4-cyclohexadienyl)acetamido]-                                7-methoxycephalosporanic acid, pivaloyloxy-                                   methyl ester                 5 kg.                                            Polyvinyl pyrrolidone       360 gm.                                           Lactose                     780 gm.                                           Talc                         80 gm.                                           Magnesium stearate           80 gm.                                           ______________________________________                                    

The active substance is mixed with the lactose and granulated with anethanol solution of the polyvinyl pyrrolidone. The wet material isscreened and admixed with the talc and magnesium stearate. The mixtureis compressed in a tableting machine to obtain 10,000 tablets weighing atotal of 630 mg. each and containing 500 mg. of active ingredient.

What is claimed is:
 1. A compound of the formula: ##SPC7##wherein the7-methoxy group is in the α-configuration; Y is hydrogen, alkyl of 1 to4 carbon atoms, or alkoxy of 1 to 4 carbon atoms; R² and R³ areindependently selected from the group consisting of hydrogen and alkylof 1 to 4 carbon atoms; n is 0, 1, 2 or 3; and R is ##SPC8## andpharmaceutically acceptable salts thereof, straight or branched chainalkyl esters of 1 to 3 carbon atoms thereof, and acyloxymethyl estersthereof having the formula ##EQU2## wherein R' is lower alkyl of 1 to 5carbon atoms, phenyl, benzyl or phenethyl.
 2. A compound of claim 1wherein n is 0 and Y is H.
 3. An acetoxymethyl ester of a compound ofclaim
 2. 4. A pivaloyloxymethyl ester of a compound of claim
 2. 5. Apharmaceutically acceptable salt of a compound of claim 1.